Regulators of the hedgehog pathway, compositions and uses related thereto

a hedgehog pathway and hedgehog gene technology, applied in the direction of drug compositions, biocides, extracellular fluid disorders, etc., can solve the problem that bmp/i>2 fails to mimic the polarizing effect of shh upon ectopic application in the chick limb bud, and achieves the effect of inhibiting smoothened-dependent pathway activation and antagonizing smoothened-dependent pathway activation

Inactive Publication Date: 2008-10-16
THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0022]One aspect of the present invention makes available methods and reagents for inhibiting smoothened-dependent pathway activation. In certain embodiments, the subject methods can be used to counteract the phenotypic effects of unwanted activation of a hedgehog pathway, such as resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function mutations. For instance, the subject method can involve contacting a cell (in vitro or in vivo) with a smoothened antagonist (defined infra), such as a steroidal alkaloid or other small molecule in an amount sufficient to antagonize a smoothened-dependent pathway activation.

Problems solved by technology

However, unlike DPP in Drosophila, Bmp2 fails to mimic the polarizing effect of Shh upon ectopic application in the chick limb bud (Francis et al.

Method used

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  • Regulators of the hedgehog pathway, compositions and uses related thereto
  • Regulators of the hedgehog pathway, compositions and uses related thereto
  • Regulators of the hedgehog pathway, compositions and uses related thereto

Examples

Experimental program
Comparison scheme
Effect test

example 1

Steroidal Compounds

[0328]Hedgehog signaling pathways are required for normal embryonic development yet also are associated with carcinogenesis (L. V. Goodrich and M. P. Scott, Neuron 21, 1243 (1998)). Loss of Sonic hedgehog signaling (Shh), for example, can result in cyclopia and other developmental defects of the face, forebrain, and other organs and structures (C. Chiang et al., Nature 383, 407 (1996)), whereas inappropriate activation of the pathway is associated with basal cell carcinoma, medulloblastoma, and other neoplastic disorders (H. Hahn et al., Cell 85, 841 (1996); R. L. Johnson et al., Science 272, 1668 (1996); M. Gailani et al., Nat Genet. 14, 78 (1996); T. Pietsch et al., Cancer Res 57, 2085 (1997); J. Reifenberger et al., Cancer Res. 58, 1798 (1998); C. Raffel et al., Cancer Res 57, 842 (1997); J. Xie et al., Nature 391, 90 (1998)). Pharmacological manipulation of this pathway thus might help elucidate the mechanisms of signal transduction and also provide a practica...

example 2

Steroid Derivatives

New Derivatives Synthesized

[0337]Cyclopamine and jervine (structures 1 and 2 of FIG. 5, respectively) are closely related plant-derived steroidal alkaloids known to specifically inhibit the Sonic hedgehog signaling pathway (Cooper et al., Science 280, p. 1603-1607, 1998). We have synthesized chemically 23 new derivatives of these two compounds, by various modifications of its secondary amine, the C-3 oxygen, and / or the C5-C6 olefin. Some of these compounds can be readily synthesized in labelled form, thus making them useful for binding studies. Some of these compounds also contain functional groups useful for photo-activatable cross-linking and consequent radiolabelling or attachment of a biotin moiety to target proteins. One of the compounds is fluorescently labelled, and may be useful for direct observation of the cellular target of cyclopamine action. The potency of the various derivatives is set forth in Table II.

TABLE IICompoundIC501>100nM2>100nM3>1μM12>10μM1...

example 3

In Vivo Testing

[0411]Methods: Female nude mice were injected subcutaneously with 5 million P2A6 fibrosarcoma cells derived from Ptc− / − embryonic fibroblasts. Three weeks after injection, each mouse had developed a discrete subcutaneous tumor. Each tumor was measured and treatments were initiated on the same day. Mice were treated once daily with intraperitoneal injections of tomatidine, cyclopamine, or KAAD-cyclopamine 33 (one mouse per treatment) for four days. The mice were killed, and tumors were measured and dissected out for histopathologic analysis. Tumor volumes were calculated as the product of length×width. The samples were paraformaldehyde-fixed and paraffin-embedded, and slides were cut for hematoxylin and eosin staining and for immunohistochemistry with polyclonal antibodies against the proliferation marker Ki-67 (Novacastra NCL-Ki67p; assay performed according to manufacturer's directions).

[0412]Results: As depicted in the graph, control treatment with tomatidine result...

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Abstract

The present invention makes available, inter alia, methods and reagents for modulating smoothened-dependent pathway activation. In certain embodiments, the subject methods can be used to counteract the phenotypic effects of unwanted activation of a hedgehog pathway, such as resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function mutations.

Description

[0001]This application is a continuation of U.S. application Ser. No. 11 / 338,503, filed Jan. 23, 2006, which is a continuation of U.S. application Ser. No. 09 / 688,076, filed Oct. 13, 2000, which is based on U.S. Provisional Applications No. 60 / 159,215, filed Oct. 13, 1999, and No. 60 / 229,273, filed Aug. 30, 2000, the specifications of which are hereby incorporated by reference in their entirety.BACKGROUND OF THE INVENTION[0002]Pattern formation is the activity by which embryonic cells form ordered spatial arrangements of differentiated tissues. The physical complexity of higher organisms arises during embryogenesis through the interplay of cell-intrinsic lineage and cell-extrinsic signaling. Inductive interactions are essential to embryonic patterning in vertebrate development from the earliest establishment of the body plan, to the patterning of the organ systems, to the generation of diverse cell types during tissue differentiation (Davidson, E., (1990) Development 108: 365-389; G...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/706C07D491/107A61K31/438A61K31/585C12N5/06C07J19/00C07H17/00A61K31/58A61P1/02A61P1/16A61P1/18A61P11/00A61P15/16A61P15/18A61P17/00A61P17/02A61P17/04A61P17/06A61P17/08A61P17/12A61P17/14A61P17/16A61P19/02A61P19/04A61P19/08A61P25/00A61P25/02A61P25/14A61P25/16A61P25/28A61P27/00A61P27/12A61P35/00A61P43/00C07J69/00
CPCC07D491/10C07D519/00C07J69/00A61K31/58C07D491/048A61K31/4355A61P1/00A61P1/02A61P1/16A61P1/18A61P11/00A61P15/00A61P15/16A61P15/18A61P17/00A61P17/02A61P17/04A61P17/06A61P17/08A61P17/12A61P17/14A61P17/16A61P19/00A61P19/02A61P19/04A61P19/08A61P21/00A61P25/00A61P25/02A61P25/14A61P25/16A61P25/28A61P27/00A61P27/12A61P35/00A61P43/00A61P7/00
Inventor BEACHY, PHILIP A.CHEN, JAMES K.TAIPALE, ANSSI JUSSI NIKOLAI
Owner THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE
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